ARID1B – Coffin-Siris Syndrome

Coffin-Siris syndrome (CSS) is a rare congenital multisystem disorder characterized by global developmental delay, intellectual disability, coarse facial features, hypertrichosis, and hypoplasia of the distal phalanx or nail of the fifth digits (PMID:22426308). ARID1B encodes a key subunit of the BAF (SWI/SNF) chromatin-remodeling complex, and haploinsufficiency of ARID1B is established as the predominant genetic cause of CSS.

Initial whole-exome sequencing of individuals with CSS identified de novo truncating ARID1B variants in three unrelated probands, and array-based copy-number analysis revealed ARID1B deletions in an additional three subjects with overlapping phenotypes, implicating ARID1B haploinsufficiency in CSS pathogenesis (PMID:22426309). Subsequent high-throughput sequencing across 63 CSS patients demonstrated that ARID1B variants account for approximately 68% of pathogenic alleles, with 68 distinct loss-of-function changes reported to date (PMID:23929686).

Inheritance of ARID1B-related CSS follows an autosomal dominant pattern, with the majority of variants arising de novo. Familial transmission has been documented in rare pedigrees, including a mother–child pair carrying the same frameshift allele, confirming segregation of pathogenic ARID1B variants with disease (PMID:27570168).

Functional studies support a loss-of-function mechanism. Patient-derived fibroblasts with heterozygous ARID1B disruption exhibit delayed cell-cycle re-entry and reduced S-phase occupancy, consistent with haploinsufficiency (PMID:24674232). Genome-wide methylation profiling (EpiSign) and machine learning facial-phenotyping have further validated the pathogenicity of non-truncating ARID1B variants by demonstrating a CSS-specific episignature and characteristic dysmorphic gestalt in carriers (PMID:37654076).

The phenotypic spectrum of ARID1B-CSS extends beyond core features to include endocrine/metabolic manifestations such as extreme obesity, macrocephaly, hepatomegaly, and hyperinsulinism, as well as polycystic ovarian syndrome, expanding diagnostic criteria (PMID:24569609). Additional neurodevelopmental comorbidities include seizures (up to 28% of cases) and variable corpus callosum anomalies.

Together, genetic and experimental evidence unequivocally establish ARID1B haploinsufficiency as the cause of Coffin-Siris syndrome. Clinical testing should prioritize ARID1B sequencing and deletion/duplication analysis in individuals with suggestive phenotypes. Future studies may refine genotype–phenotype correlations and explore targeted therapies for growth and metabolic complications.

Key Take-home: ARID1B loss-of-function variants cause autosomal dominant Coffin-Siris syndrome with a broad neurodevelopmental and multisystem phenotype, enabling definitive molecular diagnosis and guiding multidisciplinary management.

References

• Nature Genetics • 2012 • Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome PMID:22426309
• Nature Genetics • 2012 • Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome PMID:22426308
• Orphanet Journal of Rare Diseases • 2014 • Expanding the phenotypic spectrum of ARID1B-mediated disorders and identification of altered cell-cycle dynamics due to ARID1B haploinsufficiency PMID:24674232
• Genes • 2021 • Genotype-Phenotype Correlations in 208 Individuals with Coffin-Siris Syndrome PMID:34205270
• Molecular Genetics & Genomic Medicine • 2019 • De novo splice site variant of ARID1B associated with pathogenesis of Coffin-Siris syndrome PMID:31628733
• European Journal of Human Genetics • 2014 • Coffin-Siris Syndrome with obesity, macrocephaly, hepatomegaly and hyperinsulinism caused by a mutation in the ARID1B gene PMID:24569609
• American Journal of Medical Genetics Part C • 2023 • Integration of EpiSign, facial phenotyping, and likelihood ratio interpretation of clinical abnormalities in the re-classification of an ARID1B missense variant PMID:37654076

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